Candidiasis now represents the third most frequent nosocomial infection in hospitals both in the US and worldwide, and C. albicans remains the most frequent causative agent of candidiasis. Unfortunately these infections carry unacceptably high mortality rates. Candidiasis is often associated with biofilm formation and once established, biofilms have the potential to initiate or prolong infections by providing a safe sanctuary from which organisms can invade local tissue, seed new infection sites and resist eradication efforts. Biofilm accumulation results from the balance of attachment, growth, and dispersion processes. Without any question, of these phenomena, the least understood is biofilm dispersion. In the case of C. albicans this is particularly worrisome because biofilm dispersion is the step that represents the main culprit associated with life-threatening clinical infections in susceptible patients: it is precisely the detached cells that are responsible for septicemia and for dissemination to target organs prior to the establishment of invasive disease. Importantly, both of these clinical manifestations (candidemia and systemic invasive candidiasis) are associated with the high morbidity and mortality rates. Therefore, the main objective of the proposed studies is to examine the process of biofilm dispersion. To this end we will: i) identify the environmental signals associated with C. albicans biofilm dispersion, ii) identify the molecular mechanisms involved in biofilm dispersion and iii) analyze the phenotypes of yeast cells dispersed from the biofilm, with special emphasis on adhesive properties, drug resistance and virulence. The proposed research is innovative since it studies biofilms, one of the major paradigms of modern microbiology. Moreover, it focuses on a process, biofilm dispersion, that has largely been ignored in the past by C. albicans investigators. PUBLIC HEALTH RELEVANCE: Biofilm formation has severe consequences for human health. The main idea behind this study is that we need to better understand how C. albicans cells detach or separate from biofilms, since these cells are responsible for the subsequent establishment of infections in different organs. If we prevent this critical step, it may lead to a substantial reduction in morbidity, mortality and extended hospital stay, while simultaneously reducing healthcare costs.